ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1328T>G (p.Met443Arg) (rs886043236)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000327267 SCV000339046 uncertain significance not provided 2016-01-19 criteria provided, single submitter clinical testing
Counsyl RCV000673223 SCV000798401 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-03-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000673223 SCV000884960 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-06-17 criteria provided, single submitter clinical testing The ACADVL c.1328T>G; p.Met443Arg variant (rs886043236) is reported in the literature in an individual with VLCAD deficiency (Schiff 2013) who was also heterozygous for another variant classified as pathogenic in ClinVar (Variation ID: 203582); cultured fibroblasts from this individual showed no detectable VLCAD activity. Furthermore, functional analysis of p.Met443Arg expressed using an in vitro prokaryotic system yielded no activity, even though protein of the correct size was detected by western blot. Additionally, another variant at this codon (c.1328T>C; p.Met443Thr) has been reported in an individual with VLCAD deficiency (Li 2015). The p.Met443Arg variant is reported in ClinVar (Variation ID: 285852), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 443 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Li X et al. Very long-chain acyl-coenzyme A dehydrogenase deficiency in Chinese patients: eight case reports, including one case of prenatal diagnosis. Eur J Med Genet. 2015 Mar;58(3):134-9. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000673223 SCV001365098 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1328T>G (NP_000009.1:p.Met443Arg) [GRCH38: NC_000017.11:g.7223871T>G] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP3
Invitae RCV000673223 SCV001391136 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-07-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 443 of the ACADVL protein (p.Met443Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ACADVL variant in an individual affected with VLCAD (PMID: 23480858). ClinVar contains an entry for this variant (Variation ID: 285852). This variant has been reported to affect ACADVL protein function (PMID: 23480858). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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